title: Mutations in the mevalonate kinase (MVK) gene cause nonsyndromic retinitis pigmentosa.
abstract: OBJECTIVE
  Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous disorder characterized by night blindness and peripheral vision loss, and in many cases leads to blindness. Despite extensive knowledge about genes involved in the pathogenesis of RP, the genetic cause remains elusive in many patients. In this study, we aimed to identify novel genes that are involved in the cause of RP.
  
  
  METHODS
  We present a case series with mutations in the mevalonate kinase (MVK) gene.
  
  
  METHODS
  A total of 769 patients with nonsyndromic RP and 174 Dutch control individuals participated in this study.
  
  
  METHODS
  Exome sequencing analysis was performed in a proband of Dutch origin who was initially diagnosed with nonsyndromic autosomal recessive RP. Mutations in MVK were identified and subsequently tested for segregation within the patient's family and screened in a large cohort of patients with genetically unsolved RP. Patients with mutations underwent extensive clinical reexamination.
  
  
  METHODS
  Digital fundus photography, spectral-domain optical coherence tomography (OCT), and fundus autofluorescence analysis were performed in patients with MVK mutations. Mevalonate kinase (MK) enzyme activity was analyzed in cultured lymphoblastoid cells, and mevalonic acid levels were measured in urine samples.
  
  
  RESULTS
  Exome variant filtering and prioritization led to the identification of compound heterozygous mutations in MVK (p.I268T and p.A334T) in the proband and her affected brother. Screening of our nonsyndromic RP patient cohort revealed an additional individual who was homozygous for the p.A334T alteration. Clinical reevaluation of all 3 patients showed a classic form of RP with variable extraocular symptoms, such as history of recurrent childhood febrile crises in 2 patients, mild ataxia in 1, and renal failure in 1. All 3 affected individuals showed a significantly decreased MK activity and highly elevated levels of urinary mevalonic acid.
  
  
  CONCLUSIONS
  Although the MK activity in cells and mevalonic acid concentrations in urine are strongly aberrant and comparable to that in patients with systemic mevalonate kinase deficiency (MKD), only mild clinical symptoms related to this syndrome were observed in our patients. In the current article, we add another phenotype to the spectrum of diverging disorders associated with mutations in MVK.
authors.affiliation: Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Siemiatkowska
authors.affiliation: The Rotterdam Eye Hospital, Rotterdam, The Netherlands.
authors.forename: L Ingeborgh
authors.initials: LI
authors.lastname: van den Born
authors.affiliation: Department of Immunology, Erasmus University Medical Centre, Rotterdam, The Netherlands.
authors.forename: P Martin
authors.initials: PM
authors.lastname: van Hagen
authors.affiliation: Department of General Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands; Nijmegen Centre for Infection, Inflammation and Immunity (N4i), Radboud University Medical Centre, Nijmegen, The Netherlands; Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Monique
authors.initials: M
authors.lastname: Stoffels
authors.affiliation: Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands; Institute for Genetic and Metabolic Disease, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Kornelia
authors.initials: K
authors.lastname: Neveling
authors.affiliation: Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Arjen
authors.initials: A
authors.lastname: Henkes
authors.affiliation: Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Mieke
authors.initials: M
authors.lastname: Kipping-Geertsema
authors.affiliation: Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Lies H
authors.initials: LH
authors.lastname: Hoefsloot
authors.affiliation: Department of Ophthalmology, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Carel B
authors.initials: CB
authors.lastname: Hoyng
authors.affiliation: Department of General Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands; Nijmegen Centre for Infection, Inflammation and Immunity (N4i), Radboud University Medical Centre, Nijmegen, The Netherlands; Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Anna
authors.initials: A
authors.lastname: Simon
authors.affiliation: Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands; Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands; Institute for Genetic and Metabolic Disease, Radboud University Medical Centre, Nijmegen, The Netherlands; Department of Ophthalmology, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Anneke I
authors.initials: AI
authors.lastname: den Hollander
authors.affiliation: Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands; Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Frans P M
authors.initials: FPM
authors.lastname: Cremers
authors.affiliation: Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands; Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands; Institute for Genetic and Metabolic Disease, Radboud University Medical Centre, Nijmegen, The Netherlands. Electronic address: r.collin@gen.umcn.nl.
authors.forename: Rob W J
authors.initials: RWJ
authors.lastname: Collin
mesh_terms: D000328:Adult; D004252:DNA Mutational Analysis; D004596:Electroretinography; D059472:Exome / Q000235:genetics; D005260:Female; D005451:Fluorescein Angiography; D006801:Humans; D008297:Male; D008798:Mevalonic Acid / Q000652:urine; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics*; D012174:Retinitis Pigmentosa / Q000175:diagnosis / Q000235:genetics* / Q000652:urine; D041623:Tomography, Optical Coherence; D014792:Visual Acuity / Q000502:physiology
chemical_list: D017853:Phosphotransferases (Alcohol Group Acceptor); C021796:mevalonate kinase; D008798:Mevalonic Acid